Liver and Thyroid Monitoring in Ambulatory Patients Prescribed Amiodarone in 10 HMOs

BACKGROUND: Amiodarone can cause liver and thyroid toxicity, but little is known about compliance with laboratory tests to evaluate liver and thyroid function among ambulatory patients who are dispensed amiodarone. OBJECTIVES: The primary objective of this study was to identify the proportion of ambulatory patients who had liver aminotransferase and thyroid function tests during amiodarone therapy. Secondary objectives were to (1) describe factors associated with receipt of laboratory tests and (2) determine the accuracy of administrative data for assessing aminotransferase and thyroid function monitoring. METHODS: This retrospective cohort study was conducted at 10 health maintenance organizations (HMOs) for the dates of service from January 1, 1999, through June 30, 2001. Participants included 1,055 patients dispensed amiodarone for at least 180 days within this date range; these patients were not necessarily new starts on amiodarone. Administrative claims data were analyzed to assess the percentage of patients with completed alanine/aspartate aminotransferase and thyroid function tests. Depending on the HMO site, electronic or paper medical records were reviewed to evaluate the validity of administrative claims data. Logistic regression models were used to explore factors associated with receipt of laboratory tests. RESULTS: Both aminotransferase and thyroid function tests were completed in 53.3% of patients within a 210-day follow-up period that included the 180-day period of amiodarone dispensings plus 30 days. Thyroid function, with or without liver function (aminotransferase tests), was assessed in 61.9% of patients, and aminotransferase tests, with or without thyroid function, were assessed in 68.2% of patients. After adjusting for patient characteristics and site, the factor most strongly associated with having both types of laboratory tests evaluated was concomitant therapy with a statin (adjusted odds ratio (OR) 1.55; 95% confidence interval (CI), 1.05-2.29). Other factors associated with having both types of laboratory tests evaluated included the number of outpatient visits in the 6 months before the period of amiodarone dispensings (adjusted OR 1.06; 95% CI, 1.00-1.13 for each additional 5 visits) and living in a neighborhood where a higher median percentage of people had a high school or higher education (adjusted OR 1.09; 95% CI, 1.00-1.18 for every 10% increase in educational level at the block level). There was no association between monitoring and patient illness severity as measured by the number of comorbid conditions. On the basis of an evaluation of a randomly selected subset of 104 patient records, the sensitivity and specificity of automated data were 94.2% and 85.7% for aminotransferase tests and 83.3% and 81.1% for thyroid function tests, respectively. CONCLUSIONS: Approximately half of ambulatory patients dispensed amiodarone received both recommended laboratory tests for liver and thyroid function. Improved rates of testing for liver aminotransferase and thyroid function are needed for patients who receive amiodarone.

tinued. 9,10 In some situations, liver enzyme abnormalities resolve spontaneously despite continuing therapy. 9 As is true of routine laboratory monitoring of many drugs, at this time for amiodarone, it is only assumed that routine monitoring of the aminotransferase liver enzymes (alanine and/or aspartate [ALT/AST] aminotransferases) and thyroid function improves patient outcomes. Despite the lack of direct evidence linking laboratory-value monitoring to outcomes, an agreed-upon and widely recommended strategy to prevent or minimize the adverse effects of amiodarone on liver and thyroid function is to monitor aminotransferase and thyroid function in patients taking maintenance doses of the drug. 9,[13][14][15] The manufacturers recommend in product labeling "regular" or "periodic" monitoring 10,16 of these laboratory tests for all patients prescribed amiodarone. Others (see Table 1) recommend obtaining both ALT/AST and thyroid function tests ([total and/or] free thyroxine [T4] and/or thyroid-stimulating hormone [TSH] at specific frequencies; for example, every 3 or 6 months during therapy. [7][8][9][13][14][15][16][17][18] The extent to which monitoring aminotransferases and thyroid function is conducted as a patient safety measure among patients prescribed amiodarone in ambulatory practice is not well known. The few studies that evaluated liver and thyroid monitoring among patients prescribed amiodarone were conducted at single clinics and/or included fewer than 100 patients. 7,17,19 These small studies all determined that thyroid function and liver enzymes were monitored in low percentages (23%-42%) of patients. 7,17,19 The current study was therefore undertaken to determine the rates of monitoring thyroid function and liver aminotransferases among ambulatory patients dispensed amiodarone therapy across 10 sites. Secondary objectives included determining the accuracy of administrative claims data for aminotransferase and thyroid function monitoring and describing patient factors associated with monitoring. The information provided here can be used as a basis for quality improvement initiatives by individual clinicians as a reminder to monitor individual patients and by organizations to link electronic data to help ensure recommended safety monitoring in patients receiving maintenance amiodarone therapy.

ss Methods
This retrospective study included members of 10 health maintenance organizations (HMOs) receiving chronic amiodarone therapy, defined as continuing amiodarone dispensings for at least 180 days. Participating HMO sites included members of the HMO Research Network (HMORN) Center for Education and Research in Therapeutics (CERTs). The HMORN CERTs has been described elsewhere. 20 In brief, the HMORN CERTs organizations include staff, groups, networks, independent practice associations, and mixed-model HMOs that serve racially and ethnically diverse populations and provided health care for approximately 7 million people in more than 1,000 locations in the year 2000. The Institutional Review Board of each participating HMO approved this study.
The study sample was drawn from a dataset of 2,020,037 individuals, consisting of approximately 200,000 randomly selected health plan members from practices in each of the   15 Baseline, then every 6 months Amiodarone (drug evaluation) (2005) 9 Baseline, after 2-3 months of therapy and then periodically (once every few months) 10 HMOs. The sampling scheme and demographic distribution of this population have been previously described. 21 The date range of this dataset was claims with dates of service from January Because each HMO had its own administrative database platform, the format and content of the claims datasets varied by site. The study dataset was extracted using a standardized work plan distributed to, and run by, research programmers at each site. At some of the sites, claims for laboratory tests provided to hospital inpatients were not included in the study dataset.

Examples of Aminotransferase and Thyroid Function Monitoring Recommendations for Amiodarone
Recommended laboratory monitoring for liver aminotransferases was defined as the presence of an automated administrative claim/record of a laboratory test for ALT or AST within each patient' s study evaluation period. Similarly, recommended laboratory monitoring for thyroid function was defined as the presence of an administrative record of any laboratory test for TSH, triiodothyronine (T3; total and/or free), and/or T4 (total and/or free); claims for thyrotropin-releasing hormone (TRH) were also determined; none were identified for study patients) within each patient' s study evaluation period. The patient' s study evaluation period for the laboratory monitoring was the same for both ALT/AST and thyroid function; that is, the 180-day period of ongoing amiodarone therapy plus a 30-day "grace period," so monitoring within 210 days was considered to be monitoring within the recommended time period. Laboratory test dates were the dates the tests were performed or the results were reported. Codes for laboratory tests were evaluated according to standard coding methods such as the Current Procedural Terminology codes or organizationspecific codes and included codes for both single tests and for test panels that included one or more of the aminotransferase or thyroid function tests, including general health panel laboratory tests that include ALT, AST, and TSH (Table 3).
To assess the accuracy of the administrative claims data, we examined a random sample of medical records of study patients from the 10 sites. For purposes of this study, the medical record was considered the "gold standard," meaning that the medical record served as the basis of comparison and was assumed to be more accurate. The laboratory monitoring information contained within the medical records (i.e., the presence of laboratory test results and the dates the laboratory tests were reported) was considered the gold standard. Abstractors were instructed to review all information in the medical record for the time frame of interest (e.g., laboratory printouts, progress notes, information from outside consults, etc.) to ensure abstraction of ALT/AST or thyroid function testing.
The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the administrative claims data were determined in comparison with the data abstracted from the medical records. Sensitivity was defined as the proportion of patients who had an aminotransferase or thyroid function test performed that was documented in the medical record and who also had an administrative claims code for the test. Specificity was the proportion of patients who did not have an aminotransferase or thyroid function test documented in the medical record and who also did not have a claims code for the test.

Sample Selection
The PPV was the proportion of patients who had a laboratory test conducted according to administrative data that were true positives according to the medical record. The NPV was the proportion of patients who did not have a laboratory test conducted according to administrative data that were true negatives according to the medical record. HMO administrative claims and enrollment files were used to identify patient age on the date of first drug dispensing, gender, chronic diseases, hospitalizations (during the 6 months before and during the study period), outpatient visits, and concomitant drug therapy with a statin, a thiazolidinedione, or an anticonvulsant. These drugs were chosen because ALT/AST monitoring is also recommended when patients receive chronic therapy with any of them and patients who were receiving chronic therapy with any of these 3 drug classes could have received ALT/AST monitoring for that chronic therapy independent of amiodarone therapy monitoring. 22,23 The number of chronic diseases for each patient was determined using a calculation derived from medication information contained in the Chronic Disease Score method of Clark et al. that we refer to as CDsum. 24 With CDsum, the total number of chronic diseases is calculated on the basis of medications dispensed. For example, a patient dispensed only insulin and albuterol would be identified as having 2 chronic diseases. To evaluate characteristics that predicted lack of monitoring, hospitalizations and outpatient visits that occurred within 6 months prior to each study patient' s period of continued dispensings of amiodarone were identified. Outpatient visits comprise clinic appointments, visits to the clinic laboratory, and emergency department visits. Geocoding (a standardized technique to identify the coordinates of a location when the address is known) was used to provide surrogate patient-level measures of socioeconomic status (SES). For this surrogate measure of SES, the residential street address was combined with census block-level data from the 2000 U.S. Census to construct proxies of patient race, education, and household income (poverty level). 25 Descriptive statistics were computed to characterize patients, drug dispensings, and laboratory monitoring. Proportions of patients dispensed amiodarone who received laboratory monitoring and those who did not were tabulated overall and stratified by site, age group, sex, CDsum, outpatient visits, hospitalizations within the 6 months prior to the laboratory monitoring/ ongoing amiodarone therapy period, the 3 SES variables, and concomitant drug therapy. The numbers of patients receiving concomitant therapy with amiodarone plus an anticonvulsant (n = 30) or a thiazolidinedione (n = 14) were very small and, therefore, we did not further evaluate these concomitant drugs.
Statistical significance of differences was tested using the Chi-square test or Wilcoxon rank sum test.
Associations between patient characteristics and laboratory monitoring were assessed using logistic regression modeling. Characteristics considered in univariate regression models included site, age group (in 5-year increments), sex, CDsum, outpatient visits, hospitalization in the 6 months prior to the laboratory monitoring/ongoing amiodarone therapy period, the 3 SES variables, and the presence or absence of concomitant therapy with a statin. We developed a generalized estimating equations (GEE) logistic regression model with HMO site as a cluster variable. The GEE model initially included those variables with P <0.10 in the univariate regression models: age group, outpatient visits, poverty, education, and concomitant therapy with a statin. CDsum was not included in the GEE model because it correlated with outpatient visits (Spearman correlation coefficient = 0.39). Customary residual and influential statistics were examined to assess model fit and evaluate outliers. Analyses were conducted using SAS Version 9.1 (SAS Institute Inc., Cary, NC). The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.

ss Results
We identified 1,055 patients who met the study eligibility criteria for chronic amiodarone therapy (Tables 2 and 4). Both thyroid function and liver aminotransferases were monitored in 53.3% of patients (95% confidence interval [CI], 50.2%-56.3%). The 10 participating HMO sites had significant variability in monitoring, with a range across sites from 23.1% to 78.4% of patients monitored (Figure 1). Liver aminotransferases were monitored in 68.2% of patients (95% CI, 65.3%-71.1%), and thyroid function tests were monitored in 61.9% of patients (95% CI, 58.9%-64.8%). Among all patients with thyroid tests evaluated, thyroid function monitoring comprised 97.2% TSH tests and 2.8% T4 tests. Patients with and without monitoring did not differ in age, sex, estimated number of chronic diseases, hospitalization, or poverty level (Table 4). When patient characteristics and site were controlled, only 3 factors were associated with monitoring: concomitant therapy with a statin (crude odds ratio (OR), 1.55; 95% CI, 1.21-1.98; adjusted OR, 1.55; 95% CI, 1.05-2.30), number of outpatient visits in the 6 months before the period of ongoing amiodarone dispensings (crude OR, 1.07; 95% CI, 1.01-1.14; adjusted OR, 1.06; 95% CI, 1.00-1.13 for each additional 5 visits), and living in a neighborhood where a higher median percentage of people had a high school or higher education (crude OR, 1.15; 95% CI, 1.02-1.28; adjusted OR, 1.09; 95% CI, 1.00- 1.18 for every 10% increase in educational level at the block level) (scaled deviance = 1.370). There were no overly influential or outlying observations. The effect of clustering by site was small (exchangeable working correlation = 0.056). Medical records of 104 study patients prescribed chronic amiodarone therapy were abstracted. The sensitivity, specificity, PPV, and NPV of the administrative claims in comparison with the abstracted medical records for ALT/AST and thyroid function monitoring were good to excellent as shown in Table 5.

ss Discussion
We found that only about one half (53.3%) of patients receiving ongoing therapy with amiodarone had laboratory tests conducted to assess liver injury and thyroid function during an approximately 7-month period. The laboratory test findings from administrative claims data in our study were validated with medical record review. We demonstrated that administrative claims records at these sites were sufficiently sensitive and specific to be useful in determining whether laboratory testing was conducted.
Our finding that many patients prescribed amiodarone do not have recommended laboratory monitoring is important. However, the percentage of patients with laboratory monitoring in our study is actually higher than the 23% to 42% of patients documented as monitored in the small number of other published abstracts and studies. 7,17,19 Stelfox et al. found that increases in comorbidity were associated with a lower likelihood of monitoring. 7 We found no association between monitoring and the surrogate measure we used to determine the number of comorbid conditions, that is, CDsum, but these differing findings may not be directly comparable because Stelfox used a different measure of comorbidity than that used in our study (Charlson Comorbidity Index in the Stelfox et al. study and CDsum in the present study). 7 Similar to Stelfox et al., we found no association between monitoring and patients' age or sex. 7 In our study, the factor most strongly associated with a higher rate of monitoring was concomitant therapy with a statin, a drug for which ALT/AST monitoring is also recommended; patients treated with a statin had a 55% greater likelihood of receiving monitoring of both liver enzymes and thyroid function. We found  little association between monitoring rates and socioeconomic factors. These data should be interpreted with caution because we were limited by the lack of patient-level data. Although we found significant differences in educational level of those monitored compared with those who were not monitored, the absolute differences were very small.

Liver Aminotransferase and Thyroid Function Test Monitoring by HMO Site
The incidence of amiodarone-associated adverse events is dependent on both dose and duration of therapy, with risk believed primarily to exist with daily dosages exceeding 400 mg and durations of therapy exceeding 10 to 12 months . 4,9,26 Most adverse effects are mild, but toxicity of sufficient severity to require discontinuing amiodarone has been reported in up to one fourth of patients. 9,10 Liver injury with amiodarone includes, very rarely, acute hepatitis (only 13 cases reported through 2002) and liver failure (<5 reported cases), 9,10,27-29 but the liver injury seen most often is symptomatic (<3% of patients) or asymptomatic (up to 24% of patients), sometimes transient, abnormal elevation of ALT and/or AST. 7,10 Because both clinical liver disease and fatalities have occurred with amiodarone use, 28,29 patients receiving amiodarone are recommended to have routine ALT/AST monitoring. Persistent elevations in liver enzymes alert clinicians to weigh the risks and benefits of amiodarone dosage reduction or discontinuationoften weighing the risk of sudden cardiac death against the risk of liver toxicity. An elevation of ALT/AST of 2 to 3 times the upper limit of normal, or a doubling of the ALT/AST in a patient with an elevated baseline value, is cited as the level above which amiodarone dosage reduction can be appropriate. 10,19 Withdrawal of the drug does not guarantee prompt reversal of organ toxicity, however, because tissue concentrations of amiodarone persist for weeks to months following drug withdrawal; during long-term oral administration, the mean half-life following cessation of therapy is 40 to 49 days. 9,30 Both hyper-and hypothyroidism are associated with amiodarone therapy and can develop in normal thyroid glands as well as in glands with preexisting abnormalities. 10 The amiodarone molecule contains large amounts of inorganic iodine (a 600 mg per day amiodarone dosage provides 225 mg of iodide) and amiodarone-induced thyrotoxicosis occurs due to either iodineinduced excessive thyroid hormone synthesis or to a thyroid destructive process caused by the drug or iodine. 10 Amiodarone inhibits peripheral conversion of T4 to T3 with resulting increases in both serum T4 and reverse T3 accompanied by a reduction in serum T3. 10 The majority of patients remain euthyroid despite these biochemical changes, and it is important to specifically evaluate serum TSH levels to determine whether thyroid dysfunction is present. We found that the vast majority (97.2%) of the thyroid function tests obtained in patients in our study were TSH tests.
Hyperthyroidism occurs in about 2% of amiodarone-treated patients, with a higher incidence in patients with prior inadequate dietary iodine. 9 Hyperthyroidism can be especially hazardous in the patient population prescribed amiodarone because of the possibility of arrhythmia breakthrough or aggravation. 31,32 Hyperthyroidism associated with amiodarone therapy has occurred anywhere from 1 to 73 months after initiation of therapy and with amiodarone dosages ranging from 200 to 600 mg per day; thus, ongoing monitoring is important.

Limitations
A potential limitation to our study was that we primarily used health plan administrative claims data to determine whether laboratory tests were completed, and some would argue that the medical record is the more accurate source of this information. However, the sensitivity and specificity of the claims data were shown to be good to excellent for documenting completion of these tests. Also, it is possible that not all medication dispensing or laboratory testing was captured by the HMO data systems. For example, 21.8% of the patients in this study were hospitalized during the study period. The patients who were dispensed amiodarone therapy and who were hospitalized during the study follow-up period may have received laboratory tests for aminotransferase and/or thyroid function during the hospitalization that were not captured in the data available to us because laboratory tests completed during hospitalizations were contained in the dataset for only some of the participating sites. Therefore, our measured rates of laboratory monitoring may underreport actual rates of monitoring. However, if the laboratory testing information was not available in the dataset, as evidenced by the good negative predictive value (Table 5), the laboratory testing information was also not available in the medical record and therefore not available to the prescriber to use in managing the ambulatory medical care of the patient.

Accuracy of Administrative Claims Data in Comparison to the Medical Record* for Assessing Prevalence of Liver Aminotransferase and Thyroid Function Test Monitoring
Aside from the missing data for laboratory monitoring that may have occurred during a hospital stay in the follow-up period, the administrative claims data used in this study are sufficiently accurate to be useful to assess laboratory monitoring. As is true of all studies where prescriber intent is not directly determined, we could not separate laboratory tests conducted for the purpose of assessing the potential toxicity of amiodarone from laboratory tests conducted for other reasons that had nothing to do with amiodarone therapy. Further, we did not have information on amiodarone dosage and could not evaluate whether monitoring was associated with higher daily drug dosages or if dosages were adjusted based on laboratory results. Although we do not know the percentage of abnormal test results among patients in this study, we believe it would be similar to previously published percentages. 4,[9][10][11][12] In a randomized intervention trial conducted during 2003 at one of the sites that participated in the current study, 15% of patients who were prescribed amiodarone and who received thyroid and/or aminotransferase laboratory testing as a result of the study intervention had abnormal test results. 33 There is the possibility that some patients were misclassified as continuing on amiodarone therapy. On the basis of the study definition of continuing dispensings, patients with as few as 2 dispensings of amiodarone in the 180-day dispensing period were included (Table 4). For example, a study patient with only 2 dispensings could have had dispensings of amiodarone for a 90-day supply on day 1 and day 91, and discontinued therapy for some reason on day 92.
We found variation in monitoring by HMO site (Figure 1). These HMOs differ in potentially critical patient and system factors, including geographic location, race and ethnicity of members, availability of an electronic medical record, and types and extent of clinical pharmacy programs, patient safety programs, and receipt of care from multispecialty clinics. This project was not designed to explore why one participating HMO had better rates of monitoring of ALT/AST and thyroid function than did another. However, it may be useful to understand, for example, how the characteristics of the HMO where 23.1% of patients dispensed amiodarone had ALT/AST and thyroid monitoring differed from the HMO where 78.4% of patients received monitoring (Figure 1). Knowledge of organizational characteristics and programs would augment our ability to implement decision support systems or other systematic mechanisms to assist in ensuring recommended safety monitoring in patients receiving amiodarone. It is also important to recognize that these data were collected 5 to 6 years ago, and the rates of monitoring for adverse effects associated with amiodarone therapy may be different today, although monitoring recommendations do not differ from those published 5 to 6 years ago.

ss Conclusions
The percentage of ambulatory patients who are prescribed amiodarone and who receive monitoring of liver enzymes and thyroid function needs improvement. Automated, administrative claims data can be appropriate to evaluate the prevalence of aminotransferase and thyroid function monitoring, but this source of information has limitations that should be recognized.